Generation and escape of local waves from the boundary of uncoupled cardiac tissue

We aim to understand the formation of abnormal waves of activity from myocardial regions with diminished cell-to-cell coupling. In route to this goal, we studied the behavior of a heterogeneous myocyte network in which a sharp coupling gradient was placed under conditions of increasing network automaticity. Experiments were conducted in monolayers of neonatal rat cardiomyocytes using heptanol and isoproterenol as means of altering cell-to-cell coupling and automaticity respectively. Experimental findings were explained and expanded using a modified Beeler-Reuter numerical model. The data suggests that the combination of a heterogeneous substrate, a gradient of coupling and an increase in oscillatory activity of individual cells creates a rich set of behaviors associated with self-generated spiral waves and ectopic sources. Spiral waves feature a flattened shape and a pin-unpin drift type of tip motion. These intercellular waves are action-potential based and can be visualized with either voltage or calcium transient measurements. A source/load mismatch on the interface between the boundary and well-coupled layers can lock wavefronts emanating from both ectopic sources and rotating waves within the inner layers of the coupling gradient. A numerical approach allowed us to explore how: i) the spatial distribution of cells, ii) the amplitude and dispersion of cell automaticity, iii) and the speed at which the coupling gradient moves in space, affects wave behavior, including its escape into well-coupled tissue.Comment: 28 pages, 10 figures, submitted to Biophysical Journa

Human Purkinje in silico model enables mechanistic investigations into automaticity and pro-arrhythmic abnormalities

Cardiac Purkinje cells (PCs) are implicated in lethal arrhythmias caused by cardiac diseases, mutations, and drug action. However, the pro-arrhythmic mechanisms in PCs are not entirely understood, particularly in humans, as most investigations are conducted in animals. The aims of this study are to present a novel human PCs elec- trophysiology biophysically-detailed computational model, and to disentangle ionic mechanisms of human Purkinje-related electrophysiology, pacemaker activity and arrhythmogenicity. The new Trovato2020 model incorporates detailed Purkinje-specific ionic currents and Ca2+ handling, and was developed, calibrated and validated using human experimental data acquired at multiple frequencies, both in control conditions and fol- lowing drug application. Multiscale investigations were performed in a Purkinje cell, in fibre and using an experimentally-calibrated population of PCs to evaluate biological variability. Simulations demonstrate the human Purkinje Trovato2020 model is the first one to yield: (i) all key AP features consistent with human Purkinje recordings; (ii) Automaticity with funny current up-regulation (iii) EADs at slow pacing and with 85% hERG block; (iv) DADs following fast pacing; (v) conduction velocity of 160 cm/s in a Purkinje fibre, as reported in human. The human in silico PCs population highlights that: (1) EADs are caused by ICaL reactivation in PCs with large inward currents; (2) DADs and triggered APs occur in PCs experiencing Ca2+ accumulation, at fast pacing, caused by large L-type calcium current and small Na+/Ca2+ exchanger. The novel human Purkinje model unlocks further investigations into the role of cardiac Purkinje in ventricular arrhythmias through computer modeling and multiscale simulations

Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics

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Computational modeling of human sinoatrial node: what simulations tell us about pacemaking

The Sinoatrial node (SAN) is the primary pacemaker in physiological conditions. SAN tissue is characterized by auto-ryhthmicity, i.e. it does not need external stimuli to initiate its electrical activity. The auto-rhythmic behavior is due to the spontaneous slow depolarization during the diastolic phase. Understanding the biophysical mechanisms at the base of diastolic depolarization is crucial to modulate the heart rate (HR). In turn, HR modulation is fundamental to treat cardiac arrhythmias, so that atria and ventricles can fill and pump the blood properly. The overall aim of the thesis is the investigation of the underlying mechanisms responsible for the pacemaking in human. To this end, a human computational model of the action potential (AP) of the SAN was developed. Pacemaking modulation at single cell level, effects of ion channel mutations on the beating rate and propagation of the electrical trigger from SAN to atrial tissue are the faced topics The human single cell SAN model was developed starting from the rabbit SAN by Severi et al.; the parent model was updated with experimental data and automatic optimization to match the AP features reported in literature. A sensitivity analysis was performed to identify the most influencing parameters. The investigation of pacemaking modulation was carried out through the simulation of current blockade and mimicking the stimulation of the autonomic nervous system. The model was validated comparing the simulated electrophysiological effects due to ion channel mutations on beating rate with clinical data of symptomatic subjects carriers of the mutation. More insights on pacemaking mechanisms were obtained thanks to the inclusion of calcium-activated potassium currents, which link changes in the intracellular calcium to the membrane. Finally, the propagation of the AP from the SAN to the atrial tissue and the source-sink interplay was investigated employing a mono-dimensional strand composed by SAN and atrial models

The Cardiac Pacemaker Story—Fundamental Role of the Na+/Ca2+ Exchanger in Spontaneous Automaticity

The electrophysiological mechanism of the sinus node automaticity was previously considered exclusively regulated by the so-called “funny current”. However, parallel investigations increasingly emphasized the importance of the Ca$^{2+}$-homeostasis and Na+/ Ca$^{2+}$ exchanger (NCX). Recently, increasing experimental evidence, as well as insight through mechanistic in silico modeling demonstrates the crucial role of the exchanger in sinus node pacemaking. NCX had a key role in the exciting story of discovery of sinus node pacemaking mechanisms, which recently settled with a consensus on the coupled-clock mechanism after decades of debate. This review focuses on the role of the Na$^{+}$/Ca$^{2+}$ exchanger from the early results and concepts to recent advances and attempts to give a balanced summary of the characteristics of the local, spontaneous, and rhythmic Ca$^{2+}$ releases, the molecular control of the NCX and its role in the fight-or-flight response. Transgenic animal models and pharmacological manipulation of intracellular Ca$^{2+}$ concentration and/or NCX demonstrate the pivotal function of the exchanger in sinus node automaticity. We also highlight where specific hypotheses regarding NCX function have been derived from computational modeling and require experimental validation. Nonselectivity of NCX inhibitors and the complex interplay of processes involved in Ca$^{2+}$ handling render the design and interpretation of these experiments challenging

The Cardiac Pacemaker Story-Fundamental Role of the Na+/Ca2+ Exchanger in Spontaneous Automaticity

The electrophysiological mechanism of the sinus node automaticity was previously considered exclusively regulated by the so-called “funny current”. However, parallel investigations increasingly emphasized the importance of the Ca$^{2+}$-homeostasis and Na+/ Ca$^{2+}$ exchanger (NCX). Recently, increasing experimental evidence, as well as insight through mechanistic in silico modeling demonstrates the crucial role of the exchanger in sinus node pacemaking. NCX had a key role in the exciting story of discovery of sinus node pacemaking mechanisms, which recently settled with a consensus on the coupled-clock mechanism after decades of debate. This review focuses on the role of the Na$^{+}$/Ca$^{2+}$ exchanger from the early results and concepts to recent advances and attempts to give a balanced summary of the characteristics of the local, spontaneous, and rhythmic Ca$^{2+}$ releases, the molecular control of the NCX and its role in the fight-or-flight response. Transgenic animal models and pharmacological manipulation of intracellular Ca$^{2+}$ concentration and/or NCX demonstrate the pivotal function of the exchanger in sinus node automaticity. We also highlight where specific hypotheses regarding NCX function have been derived from computational modeling and require experimental validation. Nonselectivity of NCX inhibitors and the complex interplay of processes involved in Ca$^{2+}$ handling render the design and interpretation of these experiments challenging

Effect of myocyte-fibroblast coupling on the onset of pathological dynamics in a model of ventricular tissue

Managing lethal cardiac arrhythmias is one of the biggest challenges in modern cardiology, and hence it is very important to understand the factors underlying such arrhythmias. While early afterdepolarizations (EAD) of cardiac cells is known to be one such arrhythmogenic factor, the mechanisms underlying the emergence of tissue level arrhythmias from cellular level EADs is not fully understood. Another known arrhythmogenic condition is fibrosis of cardiac tissue that occurs both due to aging and in many types of heart diseases. In this paper we describe the results of a systematic insilico study, using the TNNP model of human cardiac cells and MacCannell model for (myo) fibroblasts, on the possible effects of diffuse fibrosis on arrhythmias occurring via EADs. We find that depending on the resting potential of fibroblasts (VFR), M-F coupling can either increase or decrease the region of parameters showing EADs. Fibrosis increases the probability of occurrence of arrhythmias after a single focal stimulation and this effect increases with the strength of the M-F coupling. While in our simulations, arrhythmias occur due to fibrosis induced ectopic activity, we do not observe any specific fibrotic pattern that promotes the occurrence of these ectopic sources